In my short experience with split keyboards with non standard layouts, I have observed that the right thumb gets overused.

Most split keyboards will have both the enter keys and a few modifiers in there. The kinesis 2 is particularly bad: control, alt gr, enter, page up, page down and space bar.

Regular keyboards have most mods available on the palm of the left hand, allowing palm pressing.

Another observation is that some custom keyboards like the corne have nowhere to rest the thumbs. In regular keyboards the thumb can rest on the space bar or other keys. A wrist rest relieves this problem.

Both problems are more prevalent for unusual keyboard usage patterns. As I use vim with half automated patterns, it is very common for me to do repetitive motions with enter or space, or use motions in the browser.

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